Kenji Maeda

Antiretroviral therapy (ART) has markedly improved the prognosis of people living with HIV (PLWH); however, latent viral reservoirs remain a major barrier to a cure. The “Shock and Kill” strategy aims to reactivate latent provirus with latency‐reversing agents (LRAs) and subsequently eliminate the infected cells, yet most LRAs characterized to date provide only the “shock” component. Through screening a small‐molecule library, we identified 2‐hydrido‐2,2'‐spirobi(1,3,2‐benzodioxaphosphole) (2‐HSB) as a novel candidate that both reactivates latent HIV provirus and selectively induces cytopathic effects in latently infected reservoir cell lines, thereby exhibiting a dual “Shock and Kill” activity within a single compound. Mechanistically, the HIV‐1 tat protein appears to contribute to this selectivity. At the single‐cell level, the two effects appeared largely independent, indicating that, under the conditions tested, reactivation was not a consequence of cell death and vice versa. Importantly, 2‐HSB induced viral transcription in ex vivo CD4 ⁺ T cells from ART‐suppressed PLWH. Together, these findings identify 2‐HSB as a dual‐action candidate that reactivates latent HIV‐1 and preferentially induces cytopathic effects in reservoir cell‐line models, while supporting further mechanistic and ex vivo validation in primary reservoir‐bearing cells.

Introduction: Emerging Omicron sublineages XBB.1.16 and EG.5.1.1 have caused breakthrough infections, challenging vaccine efficacy. Hybrid immunity—vaccination plus prior SARS-CoV-2 infection—augments neutralizing activity. We investigated whether innate immune responses also contribute to breakthrough prevention. Methods: We analyzed samples from a previous case-control study of 50 breakthrough infection cases and 50 controls, all adults with ≥3 mRNA vaccine doses, recruited in June 2023 during the XBB.1.5 wave in Japan. Participants were classified as hybrid immunity (prior PCR-confirmed infection or N-IgG positive), high-vaccine-induced immunity (N-IgG negative, S-IgG > 10 ⁴ U/mL), or low-vaccine-induced immunity (N-IgG negative, S-IgG < 10 ⁴ U/mL). Neutralization titers (NT ₅₀ ) were measured against ancestral SARS-CoV-2, XBB.1.16, and EG.5.1.1. Cytokines and innate markers were analyzed in serum and cell-based assays. Results: Breakthrough cases were enriched in the low-vaccine-induced immunity group, with fewer exhibiting hybrid immunity. Hybrid immunity yielded higher NT ₅₀ values than vaccine-only groups, but humoral immunity alone did not predict breakthrough infection. Cytokine analysis showed elevated IL-8 in hybrid non-breakthrough participants, with no differences in SARS-CoV-2-specific T-cell responses. Macrophages stimulated with the nucleocapsid protein induced IL-8, which promoted neutrophil chemotaxis. S100A8/A9, a neutrophil activation marker, correlated with IL-8 and was elevated in hybrid immunity. Discussion: Hybrid immunity may protect against Omicron XBB.1.16/EG.5.1.1 via IL-8–dependent macrophage–neutrophil interactions, highlighting a synergistic role of humoral and innate immunity.

We recently reported that onnamide A, a marine-derived natural compound isolated from the sponge Theonella sp., inhibits the entry process of SARS-CoV-2 infection. However, its antiviral activity against other viruses remains largely unexplored. Here, we investigated the effects of onnamide A and its structurally related analog, onnamide B, on hepatitis B virus (HBV) infection. Using iNTCP cells, a hepatoblastoma-derived cell line permissive to HBV infection, we found that onnamides A and B exhibited cytotoxicity, with CC₅₀ values of 0.53 ± 0.10 μM and 2.37 ± 0.25 μM, respectively. Following HBV infection, the levels of total HBV RNA were significantly reduced by onnamide A (IC₅₀ = 0.06 ± 0.01 μM) and onnamide B (IC₅₀ = 0.23 ± 0.06 μM). Notably, both compounds markedly decreased the levels of HBV pregenomic RNA. Furthermore, significant inhibition was particularly evident when onnamide treatment was initiated after HBV infection. Consistent with these observations, onnamides did not affect HBV binding, entry, or covalently closed circular DNA formation, but they significantly suppressed HBV RNA transcription. In particular, the transcriptional activities driven by the core and X promoters were markedly inhibited by onnamide treatment. Taken together, our findings demonstrate that onnamides possess potent anti-HBV activity and highlight their potential as candidate compounds targeting HBV RNA transcription.

Since combination antiretroviral therapy (cART) was introduced to treat human immunodeficiency virus type-1 (HIV-1)/acquired immunodeficiency syndrome (AIDS), the AIDS mortality rate has markedly decreased, and convalescence in individuals with HIV has improved drastically. However, sexual transmission has made HIV-1 a global epidemic. Sacran is a megamolecular polysaccharide extracted from cyanobacterium Aphanothece sacrum that exhibits numerous desirable characteristics for transdermic applications, such as safety as a biomaterial, a high moisture retention effect, the ability to form a film and hydrogel, and an anti-inflammatory effect. In this study, we evaluated the anti-HIV-1 effects in sacran as a barrier to HIV-1 transmission. Sacran inhibited HIV-1 infection and envelope-dependent cell-to-cell fusion. Moreover, we used a Transwell assay to confirm that sacran inhibited viral diffusion and captured viruses. The synergistic effects of sacran and other anti-HIV infection drugs were also evaluated. HIV-1 infections can be reduced through the synergistic effects of sacran and anti-HIV-1 drugs. Our study suggests using sacran gel to provide protection against HIV-1 transmission.

Since cART was introduced to treat AIDS, the mortality rate due to AIDS has markedly decreased and the convalescence of HIV-infected individuals has improved drastically. However, HIV-1 sexual transmission has made HIV become a global epidemic. Sacran is a megamolecular poly-saccharide extracted from cyanobacterium Aphanothece sacrum that exhibits numerous desirable characteristics for transdermic applications, such as safety as a biomaterial, a high moisture re-tention effect, the ability to form a film and hydrogel, and an anti-inflammatory effect. In this study, we evaluated the anti-HIV-1 effects of Sacran as a barrier to HIV transmission. Sacran inhibited HIV-1 infection and envelope-dependent cell-to-cell fusion. Moreover, we used a Transwell assay to confirm that sacran inhibited viral diffusion and captured viruses. The synergistic effects of sacran and other anti-HIV infection drugs were also evaluated.HIV-1 infections can be reduced through the synergistic effects of sacran and anti-HIV-1 drugs. Our study suggests the use of sacran gel to protect against HIV-1 transmission.

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in the body of the patient to below the detection limit, it cannot eliminate the HIV provirus integrated into the host cell genome; hence, the virus will be produced again after cART discontinuation. Therefore, research into a cure (or remission) for HIV has been widely conducted. In this review, we focus on drug development targeting cells latently infected with HIV and assess the progress including our current studies, particularly in terms of the “Shock and Kill”, and “Block and Lock” strategies.

Convalescent plasma therapy, which involves administering plasma from recovered coronavirus disease 2019 (COVID-19) patients to infected individuals, is being explored as a potential treatment for severe cases of COVID-19. This study aims to evaluate the efficacy and safety of convalescent plasma therapy in COVID-19 patients with moderate to severe illness. An open-label, single-arm intervention study was conducted without a control group. Plasma collected from recovered COVID-19 patients was administered to eligible participants. The primary endpoint was the proportion of patients who were placed on artificial ventilation or died within 14 days of transfusion. Secondary endpoints included clinical improvement, viral load measurements, and adverse event monitoring. A total of 59 cases were included in the study. The primary endpoint was evaluated by comparing the rate obtained in the study to an existing rate of 25%. The study also assessed clinical improvement, viral load changes, and safety endpoints through adverse event monitoring. Convalescent plasma therapy shows potential as a treatment option for COVID-19. This study aimed to provide evidence for the efficacy and safety of this therapy and may contribute to its future use in treating severe cases of COVID-19.